Fatigue is the most common post-treatment problem among cancer survivors, affecting a third or more of long- term survivors. Persistent fatigue in survivors may be related in part to overactivation of the inflammatory network secondary to cancer and its treatment. Furthermore, a cancer diagnosis and cancer treatments can be quite stressful, and stress and depression can directly enhance the production of proinflammatory cytokines. Diet also impacts inflammation;about one-third of the total energy intake in the United States population comes from fast food consumption that is typically high in saturated fat, and recent demonstrations of enhanced inflammation following meals high in saturated fats have sparked interest in the possibility that postprandial inflammation acts as a driver for chronic inflammation. When high-fat, fast-food-type meals flood the body with simple carbohydrates and triglycerides, the meals also trigger spikes in IL-6 and CRP. Furthermore, the proinflammatory responses that are provoked by fast-food-type meals are exaggerated by obesity, and high-fat meals push obesity's characteristic elevated inflammatory responses even higher and sustain them longer. Both obesity and inflammation are associated with a poorer prognosis in breast cancer survivors. Building on our existing prospective cancer fatigue study (R01 CA131029, Kiecolt-Glaser PI), this double-blind, randomized crossover trial will assess the association between changes in inflammation and fatigue following a fast-food-type meal (high in saturated fat) compared to a healthier meal (moderate level of fats) in breast cancer survivors and benign controls (women who had an initial abnormal test for breast cancer). The meal challenge also provides a novel and safe method to assess the impact of a transient increase in inflammation on mood and fatigue in survivors compared to controls. Specific aims: (1) To characterize the impact of a fast-food-type meal compared to a healthier meal on postprandial inflammatory responses in breast cancer survivors and benign controls, and to appraise the relative impacts of central adiposity and depressive symptoms as predictors of inflammation and fatigue;and (2) to assess whether the overactivation of the inflammatory network that appears to be related to persistent fatigue in survivors may be fueled in part by diet. By adding these additional assessments to a subgroup of women who are already being followed within our ongoing study, we leverage our well-characterized sample to address an important public health question at minimal cost. The follow-up samples collected in our longitudinal project will provide the means to assess the extent to which increases in inflammation and fatigue following a meal challenge are associated with greater inflammation and fatigue prospectively. Thus, this R21 uses a novel paradigm to assess mechanistic connections among diet, fatigue, depressive symptoms, obesity, and inflammation both cross-sectionally and longitudinally in breast cancer survivors and benign controls. The data will promote a better understanding of the ways that diet, depression, and obesity interact to kindle inflammation. PUBLIC HEALTH RELEVANCE: Inflammation is associated fatigue in breast cancer survivors, as well as with many age-related diseases. Using breast cancer survivors and benign controls from our prospective observational study, we will assess how inflammation increases following a fast-food-type meal (high in saturated fat) compared to a healthy meal in cancer survivors and controls, and we will evaluate the relative contributions of obesity, depression, and meal type as predictors of inflammation and fatigue both cross-sectionally as well as longitudinally.